Syk

For the school abbreviated SYK, see Helsingin Suomalainen Yhteiskoulu.
Spleen tyrosine kinase

PDB rendering based on 1a81.
Identifiers
Symbols SYK; DKFZp313N1010; FLJ25043; FLJ37489
External IDs OMIM: 600085 MGI: 99515 HomoloGene: 2390 GeneCards: SYK Gene
EC number 2.7.10.2
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 6850 20963
Ensembl ENSG00000165025 ENSMUSG00000021457
UniProt P43405 Q3UPF7
RefSeq (mRNA) NM_001135052.2 NM_011518
RefSeq (protein) NP_001128524.1 NP_035648
Location (UCSC) Chr 9:
93.56 – 93.66 Mb		 Chr 13:
52.68 – 52.74 Mb
PubMed search [1] [2]

Spleen tyrosine kinase, also known as Syk, is an enyzme which in humans is encoded by the SYK gene.[1][2][3]

Contents

Function

SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain.

While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within B and T cells respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor. Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, Fc Receptor, and integrins.

Clinical significance

Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells. Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs" (ITAMs) which lead to activation of Syk including Epstein Barr virus, bovine leukemia virus, and mouse mammary tumor virus.

Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of autoimmune diseases. This has been demonstrated by the orally active inhibitor fostamatinib (R788) in the treatment of rheumatoid arthritis.[4] The 6-month double-blind, placebo-controlled trial investigated clinical responses in 457 patients with rheumatoid arthritis who were not sufficiently responsive to methotrexate. The drug indeed caused a dose-dependent improvement in disease severity. The drug was however associated with an increase in the frequency in diarrhea, upper respiratory tract infections, neutropenia. Moreover R788 increased blood pressure and a concomitant increase in treatment with antihypertensive drugs. The drug is investigational and at present the final position within the broad set of antirheumatic drugs and its long-term safety are unknown.

The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in Nasopharyngeal carcinoma and head and neck cancer while other authors have suggested a tumor suppressor role in breast and gastric cancer.

Interactions

Syk has been shown to interact with PTPN6,[5][6] LYN,[7] FCGR2A,[8][9] Lck,[10] Grb2,[5][11] VAV1,[12][13][14] FYN,[15] PTK2,[16][17] Cbl gene[18][14][19] and CRKL.[20]

References

  1. ^ "Entrez Gene: SYK Spleen tyrosine kinase". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6850. 
  2. ^ Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell 71 (4): 649–62. doi:10.1016/0092-8674(92)90598-7. PMID 1423621. 
  3. ^ Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans". Immunogenetics 40 (4): 300–2. doi:10.1007/BF00189976. PMID 8082894. 
  4. ^ Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. (September 2010). "An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis.". N Engl J Med. 363 (14): 1303–12. doi:10.1056/NEJMoa1000500. PMID 20879879. 
  5. ^ a b Ganju, R K; Brubaker S A, Chernock R D, Avraham S, Groopman J E (Jun. 2000). "Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk". J. Biol. Chem. (UNITED STATES) 275 (23): 17263–8. doi:10.1074/jbc.M000689200. ISSN 0021-9258. PMID 10747947. 
  6. ^ Dustin, L B; Plas D R, Wong J, Hu Y T, Soto C, Chan A C, Thomas M L (Mar. 1999). "Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation". J. Immunol. (UNITED STATES) 162 (5): 2717–24. ISSN 0022-1767. PMID 10072516. 
  7. ^ Sidorenko, S P; Law C L, Chandran K A, Clark E A (Jan. 1995). "Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 92 (2): 359–63. doi:10.1073/pnas.92.2.359. ISSN 0027-8424. PMC 42739. PMID 7831290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=42739. 
  8. ^ Ibarrola, I; Vossebeld P J, Homburg C H, Thelen M, Roos D, Verhoeven A J (Jul. 1997). "Influence of tyrosine phosphorylation on protein interaction with FcgammaRIIa". Biochim. Biophys. Acta (NETHERLANDS) 1357 (3): 348–58. doi:10.1016/S0167-4889(97)00034-7. ISSN 0006-3002. PMID 9268059. 
  9. ^ Kim, M K; Pan X Q, Huang Z Y, Hunter S, Hwang P H, Indik Z K, Schreiber A D (Jan. 2001). "Fc gamma receptors differ in their structural requirements for interaction with the tyrosine kinase Syk in the initial steps of signaling for phagocytosis". Clin. Immunol. (UNITED STATES) 98 (1): 125–32. doi:10.1006/clim.2000.4955. ISSN 1521-6616. PMID 11141335. 
  10. ^ Thome, M; Duplay P, Guttinger M, Acuto O (Jun. 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". J. Exp. Med. (UNITED STATES) 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. ISSN 0022-1007. PMC 2192070. PMID 7539035. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2192070. 
  11. ^ Saci, Abdelhafid; Liu Wang-Qing, Vidal Michel, Garbay Christiane, Rendu Francine, Bachelot-Loza Christilla (May. 2002). "Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement". Biochem. J. (England) 363 (Pt 3): 717–25. doi:10.1042/0264-6021:3630717. ISSN 0264-6021. PMC 1222524. PMID 11964172. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1222524. 
  12. ^ Deckert, M; Tartare-Deckert S, Couture C, Mustelin T, Altman A (Dec. 1996). "Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product". Immunity (UNITED STATES) 5 (6): 591–604. doi:10.1016/S1074-7613(00)80273-3. ISSN 1074-7613. PMID 8986718. 
  13. ^ Song, J S; Gomez J, Stancato L F, Rivera J (Oct. 1996). "Association of a p95 Vav-containing signaling complex with the FcepsilonRI gamma chain in the RBL-2H3 mast cell line. Evidence for a constitutive in vivo association of Vav with Grb2, Raf-1, and ERK2 in an active complex". J. Biol. Chem. (UNITED STATES) 271 (43): 26962–70. doi:10.1074/jbc.271.43.26962. ISSN 0021-9258. PMID 8900182. 
  14. ^ a b Bertagnolo, V; Marchisio M, Brugnoli F, Bavelloni A, Boccafogli L, Colamussi M L, Capitani S (Apr. 2001). "Requirement of tyrosine-phosphorylated Vav for morphological differentiation of all-trans-retinoic acid-treated HL-60 cells". Cell Growth Differ. (United States) 12 (4): 193–200. ISSN 1044-9523. PMID 11331248. 
  15. ^ Deckert, M; Elly C, Altman A, Liu Y C (Apr. 1998). "Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases". J. Biol. Chem. (UNITED STATES) 273 (15): 8867–74. doi:10.1074/jbc.273.15.8867. ISSN 0021-9258. PMID 9535867. 
  16. ^ Chung, J; Gao A G, Frazier W A (Jun. 1997). "Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3". J. Biol. Chem. (UNITED STATES) 272 (23): 14740–6. doi:10.1074/jbc.272.23.14740. ISSN 0021-9258. PMID 9169439. 
  17. ^ Sada, K; Minami Y, Yamamura H (Sep. 1997). "Relocation of Syk protein-tyrosine kinase to the actin filament network and subsequent association with Fak". Eur. J. Biochem. (GERMANY) 248 (3): 827–33. doi:10.1111/j.1432-1033.1997.00827.x. ISSN 0014-2956. PMID 9342235. 
  18. ^ Lupher, M L; Rao N, Lill N L, Andoniou C E, Miyake S, Clark E A, Druker B, Band H (Dec. 1998). "Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323". J. Biol. Chem. (UNITED STATES) 273 (52): 35273–81. doi:10.1074/jbc.273.52.35273. ISSN 0021-9258. PMID 9857068. 
  19. ^ Melander, Fredrik; Andersson Tommy, Dib Karim (Mar. 2003). "Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils". Biochem. J. (England) 370 (Pt 2): 687–94. doi:10.1042/BJ20021201. ISSN 0264-6021. PMC 1223185. PMID 12435267. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1223185. 
  20. ^ Oda, A; Ochs H D, Lasky L A, Spencer S, Ozaki K, Fujihara M, Handa M, Ikebuchi K, Ikeda H (May. 2001). "CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk". Blood (United States) 97 (9): 2633–9. doi:10.1182/blood.V97.9.2633. ISSN 0006-4971. PMID 11313252. 

Further reading

  • Turner M, Schweighoffer E, Colucci F, et al. (2000). "Tyrosine kinase SYK: essential functions for immunoreceptor signalling.". Immunol. Today 21 (3): 148–54. doi:10.1016/S0167-5699(99)01574-1. PMID 10689303. 
  • Fruman DA, Satterthwaite AB, Witte ON (2000). "Xid-like phenotypes: a B cell signalosome takes shape.". Immunity 13 (1): 1–3. doi:10.1016/S1074-7613(00)00002-9. PMID 10933389. 
  • Yanagi S, Inatome R, Takano T, Yamamura H (2001). "Syk expression and novel function in a wide variety of tissues.". Biochem. Biophys. Res. Commun. 288 (3): 495–8. doi:10.1006/bbrc.2001.5788. PMID 11676469. 
  • Tohyama Y, Yamamura H (2006). "Complement-mediated phagocytosis--the role of Syk.". IUBMB Life 58 (5-6): 304–8. doi:10.1080/15216540600746377. PMID 16754322. 
  • Schymeinsky J, Mócsai A, Walzog B (2007). "Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications.". Thromb. Haemost. 98 (2): 262–73. PMID 17721605. 

External links